TREM2 stabilizing antibodies

Abstract

The present invention provides antibodies that bind to and stabilize human Triggering Receptor Expressed on Myeloid cells 2 (TREM2) protein and methods of using these antibodies.

The invention claimed is: 
     
         1 . A nucleic acid molecule or set of nucleic acid molecules encoding an anti-TREM2 antibody or antigen-binding fragment thereof, wherein the anti-TREM2 antibody or antigen-binding fragment thereof comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein:
 (i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 7, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 5, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 6, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 17, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 18, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 19, as defined by the Kabat numbering system;   (ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 8, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 9, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 6, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 20, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 21, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 22, as defined by the Chothia numbering system;   (iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 10, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 11, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 12, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 23, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 21, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 19, as defined by the IMGT numbering system;   (iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 4, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 5, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 6, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 17, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 18, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 19, as defined by the Combined numbering system.   
     
     
         2 . The nucleic acid molecule or set of nucleic acid molecules of  claim 1 , wherein the anti-TREM2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 24. 
     
     
         3 . The nucleic acid molecule or set of nucleic acid molecules of  claim 1 , wherein the anti-TREM2 antibody or antigen-binding fragment thereof comprises a modified Fc domain that has reduced antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) activity compared to the antibody or antigen-binding fragment thereof without the modified Fc domain. 
     
     
         4 . The nucleic acid molecule or set of nucleic acid molecules of  claim 1 , wherein the anti-TREM2 antibody or antigen-binding fragment thereof comprises:
 a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 26.   
     
     
         5 . The nucleic acid molecule or set of nucleic acid molecules of  claim 4 , wherein:
 the heavy chain variable region is encoded by the nucleic acid sequence of SEQ ID NO: 28 and the light chain variable region is encoded by the nucleic acid sequence of SEQ ID NO: 31.   
     
     
         6 . A vector comprising the nucleic acid molecule or set of nucleic acid molecules of  claim 1 . 
     
     
         7 . The vector of  claim 6 , wherein the vector is selected from a DNA vector, an RNA vector, a plasmid, a cosmid, or a viral vector. 
     
     
         8 . A cell comprising the nucleic acid molecule or set of nucleic acid molecules of  claim 1 . 
     
     
         9 . A method of producing an anti-TREM2 antibody or antigen-binding fragment thereof, the method comprising: (i) culturing the cell of  claim 8  under conditions suitable to produce an anti-TREM2 antibody or antigen-binding fragment thereof and (ii) isolating the anti-TREM2 antibody or antigen-binding fragment thereof from the culture. 
     
     
         10 . The nucleic acid molecule or set of nucleic acid molecules of  claim 4 , wherein the heavy chain is encoded by the nucleic acid sequence of SEQ ID NO: 38 and the light chain is encoded by the nucleic acid sequence of SEQ ID NO: 32.